15-89320890-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_002693.3(POLG):​c.2857C>T​(p.Arg953Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

18
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9U:1

Conservation

PhyloP100: 9.60
Variant links:
Genes affected
POLG (HGNC:9179): (DNA polymerase gamma, catalytic subunit) Mitochondrial DNA polymerase is heterotrimeric, consisting of a homodimer of accessory subunits plus a catalytic subunit. The protein encoded by this gene is the catalytic subunit of mitochondrial DNA polymerase. The encoded protein contains a polyglutamine tract near its N-terminus that may be polymorphic. Defects in this gene are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.97
PP5
Variant 15-89320890-G-A is Pathogenic according to our data. Variant chr15-89320890-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 194838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLGNM_002693.3 linkc.2857C>T p.Arg953Cys missense_variant Exon 18 of 23 ENST00000268124.11 NP_002684.1 P54098E5KNU5
POLGNM_001126131.2 linkc.2857C>T p.Arg953Cys missense_variant Exon 18 of 23 NP_001119603.1 P54098E5KNU5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLGENST00000268124.11 linkc.2857C>T p.Arg953Cys missense_variant Exon 18 of 23 1 NM_002693.3 ENSP00000268124.5 P54098

Frequencies

GnomAD3 genomes
AF:
0.0000986
AC:
15
AN:
152192
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000362
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251172
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135768
show subpopulations
Gnomad AFR exome
AF:
0.000246
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000889
AC:
13
AN:
1461620
Hom.:
0
Cov.:
35
AF XY:
0.00000825
AC XY:
6
AN XY:
727118
show subpopulations
Gnomad4 AFR exome
AF:
0.000209
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000986
AC:
15
AN:
152192
Hom.:
0
Cov.:
33
AF XY:
0.0000807
AC XY:
6
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.000362
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000649
Hom.:
0
Bravo
AF:
0.0000982
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3Uncertain:1
Aug 18, 2021
Athena Diagnostics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. -

Jan 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

POLG: PM2, PM3, PP1:Moderate, PP3 -

Feb 06, 2015
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: clinical testing

- -

Jun 26, 2023
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Observed with a pathogenic variant in an adult with peripheral neuropathy, ophthalmoparesis/CPEO, ptosis, COX deficiency, ragged-red fibers, migraines, diarrhoea, lactic acidosis, hypotonia, ataxia, seizures, exercise intolerance, muscle weakness, muscle cramps, optic atrophy, and easy fatigability, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Tang et al., 2011); Reported in an individual with adult onset PEO, ptosis, muscle weakness, hypothyreosis, ataxia, asthma and balance disturbance; however, information on the zygosity of the variant was not provided and parental studies were not performed (Luoma et al., 2004); De novo variant with confirmed parentage in a patient referred for genetic testing at GeneDx; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25203713, 24122062, 20185557, 21880868, 22334187, 15351195, 20701905, 28480171, 25724872, 21993618, 35114397, 31665838, 33434755, Crawford2022[casereport], 27381400, 22617125, 27748512, 22334185, 29992832, 18321754, 33513296) -

Progressive sclerosing poliodystrophy Pathogenic:3
Feb 17, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 01, 2018
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The NM_002693.2:c.2857C>T (NP_002684.1:p.Arg953Cys) [GRCH38: NC_000015.10:g.89320890G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. PS3:Well established functional studies show a deleterious effect on POLG. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic. -

Sep 03, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 953 of the POLG protein (p.Arg953Cys). This variant is present in population databases (rs11546842, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal recessive progressive external ophthalmoplegia (PMID: 21880868, 22334187, 33046616). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 194838). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt POLG protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect POLG function (PMID: 20185557). This variant disrupts the p.Arg953 amino acid residue in POLG. Other variant(s) that disrupt this residue have been observed in individuals with POLG-related conditions (PMID: 31665838), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Pathogenic:1
May 04, 2021
Centogene AG - the Rare Disease Company
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

POLG-Related Spectrum Disorders Pathogenic:1
Jul 10, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: POLG c.2857C>T (p.Arg953Cys) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family A, palm domain (IPR001098) of the encoded protein sequence. This alters a highly conserved residue in which other missense variants have been found in association with disease (HGMD), suggesting this may be a functionally important region of the protein. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251172 control chromosomes (gnomAD). c.2857C>T has been reported in the literature in multiple individuals affected with POLG-Related Spectrum Disorders (Gurgel-Giannetti_2012, Luoma_2016, Paul_2020, Tang_2012, Wahbi_2015), and some patients were reported as compound heterozygous with other likely pathogenic variants. These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. One found that the orthologous variant in yeast did not increase the number of colonies unable to perform aerobic respiration (Stumpf_2010), while another study found that the variant resulted in a sharply reduced efficiency of dCTP incorporation in vitro (Li_2016). The following publications have been ascertained in the context of this evaluation (PMID: 22334187, 15351195, 21993618, 26224072, 20185557, 33046616, 27381400). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic (n=1), likely pathogenic (n=4), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

POLG-related disorder Pathogenic:1
Mar 28, 2024
PreventionGenetics, part of Exact Sciences
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The POLG c.2857C>T variant is predicted to result in the amino acid substitution p.Arg953Cys. This variant was originally reported in an individual with progressive external ophthalmoplegia (PEO) as well as muscle weakness, ataxia, asthma, and hypothyroidism (Luoma et al. 2004. PubMed ID: 15351195). However, it has also been observed in the compound heterozygous state in an individual with mitochondrial neurogastrointestinal encephalomyopathy (Tang et al. 2011. PubMed ID: 21993618), as well as in the compound heterozygous state in three siblings with PEO with additional features (Gurgel-Giannetti et al. 2012. PubMed ID: 22334187). This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD. An alternate nucleotide change affecting the same amino acid (p.Arg953His) have been reported in association with POLG-deficiency (Tchikviladzé et al. 2015. PubMed ID: 25118206). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
31
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.98
D;D
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
.;D
M_CAP
Pathogenic
0.68
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.5
H;H
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-7.9
D;D
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.93
MVP
0.99
MPC
0.77
ClinPred
0.90
D
GERP RS
5.2
Varity_R
0.92
gMVP
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs11546842; hg19: chr15-89864121; API